Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial

Abstract

SUMMARYThe NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was À1.5 (1.7)ml/min with everolimus versus À7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.

Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy

“…Increased rate of biopsy‐proven acute rejection without hemodynamic compromise was noted in the CNI‐free arm. Similar results on renal function were found in the NOCTET trial in patients randomized to everolimus with reduced‐dose CNI > 1 year after transplant and in other studies in which patients were randomized late after transplant to a CNI‐free regimen …”

Renal protection strategies after heart transplantation

“…A subanalysis revealed a significantly higher renal function improvement in patients treated with ERL and mGFRs of 20‐29 and 30‐59 mL/min/1.73 m 2 . This effect was not seen in the control group and in patients with mGFR of 60‐89 mL/min/1.73 m 2 . These controversial results for CNI reduction were also confirmed in the meta‐analysis of eight open‐label studies (n = 723).…”

Individualizing immunosuppression in lung transplantation

“…Importantly, at last follow-up ≥5 years post-randomization, lung transplant patients showed no between-group difference and a similar decline in mean GFR. Pneumonia also was reported to occur more in everolimus treated lung transplant patients versus controls (33.3% vs 9.5%) 53 . In addition to high rates of pneumonia in clinical studies, interstitial pneumonitis is an infrequent but potentially fatal complication of mTOR inhibitors and requires prompt discontinuation of therapy 54,55 .…”